U.S. Pat. No. 4,636,505 describes N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds, methods for their preparation, and their utility in the treatment of malignant or benign prostatic disease or of androgen dependent disease conditions such as acne, hirsutism or seborrhoea. Bicalutamide, (xc2x1)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide, is a particularly preferred specie of the above compounds. Bicalutamide is an effective, well-tolerated and convenient non-steroidal antiandrogen for use in the treatment of advanced prostate cancer. Preclinical and clinical studies have also indicated its potential as monotherapy, with quality of life advantages compared with castration (Schellhammer, Exp. Opin. Invest. Drugs, 8, p. 849 (1999)).
Bicalutamide has been prepared by reacting 3-trifluoromethyl-4-cyanoanaline with methacryloyl chloride followed by epoxidation of the resultant N-(3-trifluoromethyl-4-cyanophenyl)methacrylamide and subsequent epoxide ring opening with thiol and sulfone formation (U.S. Pat. No. 4,636,505; Tucker et al., J. Med. Chem., 31, p. 954 (1988)). Although that process is relatively straight forward, chromatographic separations required in the process makes it undesirable for use on a commercial scale. In addition, that process requires the use of relatively expensive starting materials.
Accordingly, what is needed in the art is a process for the preparation of N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds which does not require the use of chromatographic separations and uses less expensive starting materials.
It is, therefore, an object of the present invention to provide an improved process for the preparation of N-(substituted phenyl)-3-alkyl-, aryl- and heteroarylsulfonyl-2-hydroxy-2-alkyl- and haloalkylpropanamide compounds which does not require the use of chromatographic separations and uses relatively less expensive starting materials compared to the art processes.
This and other objects and features of the present invention are described hereinbelow in more detail.
The present invention provides an improved process for the preparation of an N-(substituted phenyl)-3-alkyl-, aryl- or heteroarylsulfonyl-2-hydroxy-2-alkyl- or haloalkylpropanamide of formula I 
wherein
Y is cyano, nitro, perfluoroalkyl, alkylcarbonyl, alkoxycarbonyl or alkylsulfonyl;
R is perfluoroalkyl, cyano, nitro, alkylcarbonyl, alkoxycarbonyl, alkyl or alkoxy;
R1 is alkyl or haloalkyl; and
R2 is alkyl, aryl or heteroaryl,
which process comprises:
(a) reacting a substituted benzene of formula II (II) 
xe2x80x83wherein Y and R are as described above, X is F, Cl, Br, I or xe2x80x94OSO2R3, and R3 is alkyl or aryl with an xcex1,xcex2,-unsaturated propanamide of formula III 
xe2x80x83wherein R1 is as described above in the presence of a first base to form an N-(substituted phenyl)-xcex1,xcex2-unsaturated propanamide of formula IV 
(b) reacting the formula IV propanamide with an epoxidizing agent to form an epoxide of formula V 
(c) reacting the formula V epoxide with a thiol of formula VI
R2SHxe2x80x83xe2x80x83(VI) 
xe2x80x83wherein R2 is as described above in the presence of a second base to form a sulfide of formula VII 
(d) reacting the formula VII sulfide with an oxidizing agent.
The present invention also relates to improved processes for the preparation of N-(substituted phenyl)-xcex1,xcex2-unsaturated propanamides of formula IV, epoxides of formula V, and sulfides of formula VII.
The process of the present invention preferably comprises reacting a substituted benzene of formula II with an xcex1,xcex2-unsaturated propanamide of formula III in the presence of a first base and an aprotic solvent, preferably in a temperature range from about xe2x88x9240xc2x0 C. to 155xc2x0 C., to form an N-(substituted phenyl)-xcex1,xcex2-unsaturated propanamide of formula IV; reacting the formula IV propanamide with an epoxidizing agent in the presence of an aprotic solvent, preferably in a temperature range from about xe2x88x9278xc2x0 C. to 155xc2x0 C., to form an epoxide of formula V; reacting the formula V epoxide with a thiol of formula VI in the presence of a second base and an aprotic solvent, preferably in a temperature range from about xe2x88x9278xc2x0 C. to 155xc2x0 C., to form a sulfide of formula VII; and reacting the formula VII sulfide with an oxidizing agent in the presence of an aprotic solvent, preferably in a temperature range from about xe2x88x9278xc2x0 C. to 155xc2x0 C.
Aprotic solvents suitable for use in this invention include, but are not limited to, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, chloroform, 1,2-dichloroethane, and the like; hydrocarbons such as hexane, heptane, and the like; aromatic hydrocarbons such as benzene, toluene, a xylene, mesitylene, and the like; halogenated aromatic hydrocarbons such as fluorobenzene, chlorobenzene, bromobenzene, a dihalobenzene, and the like; an ether such as diethyl ether, methyl t-butyl ether, tetrahydrofuran, and the like; an ester such as ethyl acetate, and the like; and an amide such as N,N-dimethylformamide, and the like; and mixtures thereof. In a preferred embodiment of the present invention, step (a) is conducted in the presence of an amide, preferably N,N-dimethylformamide; step (b) is conducted in the presence of a halogenated hydrocarbon, preferably dichloromethane; step (c) is conducted in the presence of an ether, preferably tetrahydrofuran; and step (d) is conducted in the presence of a halogenated hydrocarbon, preferably dichloromethane.
First and second bases useful in the processes of this invention include, but are not limited to, alkali metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, and the like; alkali metal amides such as sodium amide, and the like; and alkyllithiums such as butyllithium, and the like. Preferred first and second bases include sodium hydride, potassium t-butoxide, sodium amide, and butyllithium with sodium hydride being more preferred.
Epoxidizing agents suitable for use in the present invention include conventional epoxidizing agents known in the art. Conventional epoxidizing agents particularly useful in the processes of this invention include, but are not limited to, peracids such as peracetic acid, trifluoroperacetic acid, 3-chloroperbenzoic acid, and the like; and dioxiranes such as dimethyldioxirane, methyltrifluoromethyldioxirane, and the like. Preferred epoxidizing agents include peracids with trifluoroperacetic acid being more preferred.
Oxidizing agents suitable for use in the oxidation of the formula VII sulfides of this invention include conventional oxidizing agents known in the art. Conventional oxidizing agents particularly useful for the oxidation of the formula VII sulfide of the present invention include, but are not limited to, peracids such as peracetic acid, trifluoroperacetic acid, 3-chloroperbenzoic acid, and the like; dioxiranes such as dimethyldioxirane, methyltrifluoromethyldioxirane, and the like; hydrogen peroxide; sodium periodate; N-methylmorpholine N-oxide; and oxone. Preferred oxidizing agents include peracids with trifluoroperacetic acid being more preferred.
The peracids utilized in the epoxidation and oxidation steps of the present invention may be conveniently prepared in situ from hydrogen peroxide and the corresponding acid anhydride. For example, trifluoroperacetic acid is preferably formed in situ from hydrogen peroxide and trifluoroacetic anhydride.
In a preferred process of the present invention, R3 is trifluoromethyl. In another preferred process of this invention, X is F, Cl, Br or I, more preferably F.
Preferred formula I compounds produced by the process of the present invention are those wherein
Y is cyano, nitro or trifluoromethyl;
R is trifluoromethyl, cyano, nitro, methoxy or methyl;
R1 is methyl or trifluoromethyl; and
R2 is alkyl,
phenyl optionally substituted with one fluoro, chloro, cyano, nitro, methoxy or methylthio substituent, or
thienyl, imidazolyl, thiazolyl, benzothiazolyl, thiadiazolyl, pyridyl or pyrimidinyl each optionally substituted with one chloro, bromo or methyl substituent.
More preferred formula I compounds prepared by the process of this invention are those wherein
Y is cyano or nitro;
R is trifluoromethyl;
R1 is methyl; and
R2 is C1-C4alkyl, phenyl, p-fluorophenyl, thiazol-2-yl, 4-methylthiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl or 2-pyridyl.
The process of the present invention is particularly useful for the preparation of bicalutamide.
Optical isomers of the formula I compounds may be obtained by conducting the step (b) epoxidation under asymmetric conditions to give chiral compounds. For example, the formula IV propanamide may be epoxidized with a chiral dioxirane to give a chiral epoxide.
Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.
It should be noted that any heteroatom with unsatisfied valences is assumed to have the hydrogen atoms necessary to satisfy the valences.
The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 12 carbon atoms unless otherwise defined. An alkyl group is an optionally substituted straight, branched or cyclic saturated hydrocarbon group. When substituted, alkyl groups may be substituted with up to four substituent groups, R4 as defined, at any available point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with xe2x80x9cbranched alkyl groupxe2x80x9d. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo (such as F, Cl, Br or I), haloalkyl (such as CCl3 or CF3), alkoxy, alkylthio, hydroxy, carboxy (xe2x80x94COOH), alkoxycarbonyl, alkylcarbonyloxy, amino (xe2x80x94NH2), carbamoyl, urea, amidinyl or thiol (xe2x80x94SH).
The terms xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkylthioxe2x80x9d, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (xe2x80x94Oxe2x80x94) or a sulfur linkage (xe2x80x94Sxe2x80x94), respectively.
Sulfonyl denotes groups bonded by xe2x80x94SO2-linkages.
The term xe2x80x9calkoxycarbonylxe2x80x9d, as used herein, denotes an alkoxy group bonded through a carbonyl group.
The term xe2x80x9calkylcarbonylxe2x80x9d refers to an alkyl group bonded through a carbonyl group.
The term xe2x80x9carylxe2x80x9d refers to monocyclic or bicyclic aromatic rings, e.g., phenyl, substituted phenyl and the like, as well as groups which are fused, e.g., napthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. Aryl groups may optionally be substituted with one or more groups including, but not limited to, halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, nitro, trifluoromethyl, amino, cyano, alkyl S(O)t (t=0, 1 or 2) or thiol.
The term xe2x80x9cheteroarylxe2x80x9d refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, O, S, or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from O or S, and in which 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Exemplary heteroaryl groups include the following: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, thiadiazolyl, thiazolyl, oxazolyl, triazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyrazinyl, tetrazolyl, pyridazinyl, pyrimidinyl, triazinylazepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl and benzofurazanyl. Exemplary substituents include one or more of the following: halogen, alkyl, alkoxy, hydroxy, carboxy, carbamoyl, alkoxycarbonyl, trifluoromethyl, nitro, cyano, amino, alkylS(O)t(t=0, 1 or 2) or thiol.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d refers to chlorine, bromine, fluorine or iodine.
The term xe2x80x9cperfluoroalkylxe2x80x9d refers to a CnF2n+1 group wherein n is an integer of 1 to 6.
Starting compounds of formulas II and III are known to those skilled in the art. Those starting compounds may be prepared by procedures known in the art or are commercially available.
In order to facilitate a further understanding of the invention, the following examples are presented primarily for the purpose of illustrating more specific details thereof. The scope of the invention should not be deemed limited by the examples, but encompasses the entire subject matter defined in the claims.